Viral myocarditis is inflammation of heart muscle caused by or associated with various viruses, which induce focal or diffuse inflammatory exudation in interstitial myocardium and degeneration, necrosis or lysis of cardiac muscle fiber. Viral myocarditis may be complicated by pericarditis or endocarditis. The outcome of viral myocarditis includes myocardial damage, heart dysfunction, arrhythmia and systemic symptoms. Viral myocarditis occurs at any age. In recent years, the incidence of viral myocarditis is increasing. The sequela of acute viral myocarditis include arrhythmia, heart failure, cardiac shock, and even sudden death. The disease may be prolonged with cardiac hypertrophy and permanent cardiac muscle injury. Cardiomyopathy finally results from immune reaction. The treatment of viral myocarditis includes antibiotics, heart protective agents, antioxidant such as high dose vitamin C, vitamin E, coenzyme Q10, nutrients for myocardium such as energy combination to provide enough nutrition for myocardium. These measures are applied to improve heart function, repair cardiac damage, and prevent heart failure, but the efficacy is not so ideal, especially for the structural and functional changes in myocarditis. No reliable therapy is available for these pathological changes.
Dilated (congestive) cardiomyopathy (DCM) is the eventual outcome of various myocardial diseases of unidentified origin. Its pathological changes are non-rheumatic, non-hypertensive and not due to coronary heart disease. The main clinical features of dilated cardiomyopathy is ventricular hypertrophy, myocardial pump function failure, or congestive heart failure. Hypertrophy of nucleus and organelles is generally seen in mild myocardium damage of dilated cardiomyopathy. Structural change, cell death and the resultant fibrosis is usually seen in severe damage. The etiology and pathogenesis of DCM remains to be clarified. The prognosis of DCM is very poor because no effective therapy is available. Most of such patients die of increasingly worsen heart failure. Sudden death may result from arrhythmia. At present, no specific effective therapy is available for DCM. The routine treatment for DCM includes administration of cardiac tonics, diuretics, ACEI and other drugs. In addition, third generation calcium antagonist amlodipine and third generation β-receptor antagonist such as carvedilol are also used to treat DCM. It is controversial about the effect of thyroxin and growth hormone because no randomized double-blind clinical trial evidence is available. Volume reduction surgery of left ventricle can decrease the inside diameter of left ventricle and improve cardiac function temporarily. However, the higher mortality associated with post-operational heart failure and arrhythmia hampers the application of this method. Dynamic cardiomyoplasty is useful in improving cardiac function, but patient can not tolerate the relatively extensive trauma. Therefore, this operation is only used as alternative to heart transplant. In surgery, heart transplant is radical treatment for DCM. However, lack of donor heart, expensive cost, post-operation infection and transplant rejection are the main obstacles. Therefore, new therapy for DCM is urgently needed in clinical practice.
Doxorubicin or adriamycin (ADM) belongs to anthracycline anticancer agents with a broad spectrum and potent anti-tumor activity. It has been widely used in clinical practice to treat various malignant tumors such as lung cancer, breast cancer, bladder carcinoma, testis carcinoma, thyroid cancer, soft tissue carcinoma, osteosarcoma, neuroblastoma, acute leukemia, malignant lymphoma, gastric carcinoma, liver cancer, esophageal carcinoma, and cervical carcinoma. ADM acts through incorporation with DNA to inhibit DNA synthesis. The inhibition effect is observed in S, M, G1 and G2 phases, but the activity is most active in S phase. It has been discovered that a higher dose of chemotherapy agents produces better clinical efficacy and longer survival in unit time for breast cancer patients, whether metastatic or post-operative chemotherapy. Other studies have confirmed the importance of higher dose and dose potency, as well as the relation between dose, dose potency and efficacy.
However, the application of ADM is restricted by its toxic side effects. The toxicity of ADM includes bone marrow depression. In about 60-80% patients, leukocyte and platelet counts decrease to the lowest level 10-15 days after administration, and recover to normal levels 21 days later. Major digestive tract reaction are nausea, vomiting, anorexia, gastritis and even ulcer and stomatitis. Alopecia also occurs in nearly all patients treated with ADM, although this effect can be reversed after withdrawal.
More importantly, the major factor preventing clinical application of higher dose ADM and other anthracycline agents is cardiac toxicity. Cardiac toxicity of ADM may result from the production of oxygen-derived free radicals. The semiquinone group in ADM can induce an oxidoreduction reaction, which leads to enhanced lipid peroxidation, contributing to cellular damage. The free radicals damage cell membrane and organelle membrane, and modify the function of membrane proteins and enzyme activity. These changes can lead to intracellular calcium overload, inhibition of DNA and protein synthesis, and energy metabolism disorder, which inevitably harm the cardiac contraction and relaxation process.
Cardiac toxicity occurs when ADM accumulates in the body because ADM has a higher affinity for cardiac tissue than for other tissues. Thus, the heart is more vulnerable to the toxic effect of ADM. Cardiac toxicity may be acute or chronic. Clinical features of acute cardiac toxicity include cardiac functional changes, such as sinus tachycardia, arrhythmia, conduction block, ST-T segment alteration, etc. Various arrhythmia may be present at early stages of ADM therapy. Acute cardiac toxicity can also include decrease of the left ventricular ejection fraction (LVEF), as well as decreases in stroke volume (SV), cardiac output (CO) and cardiac index (CI). ADM has also been suggested to inhibit the contraction and pumping ability of the left ventricle. Chronic cardiac toxicity include irreversible congestive heart failure. Once a person suffers from congestive heart failure, the mortality decreases to about 30% to 50%. Because of the cardiac toxicity associated with ADM, some patients have to terminate ADM therapy, or reduce the dosage or length of ADM use, affecting the efficacy of ADM therapy.
Studies have been conducted to find ways to reduce the toxicity of ADM, while maintaining the therapeutic effect. Certain measures, such as decreasing the total dose of ADM or administering myocardial nutrients such as a high dose of vitamin C, may be helpful in protecting myocardium. Regular blood transfusion and administering an iron chelating agent ICRF-187 also have some effect in protecting myocardium. However, although these supportive agents are beneficial to the cardiac muscle, they have little effect on the cardiac toxicity induced by ADM. Thus, there exists a need in the art for preventing, treating or delaying the cardiac toxicity of ADM without affecting its efficacy.
Heart failure is caused by many etiology such as coronary arteriosclerosis, hypertension and inflammation induced myocardial injury, finally leading to refractory heart disease. These factors cause changes in myocardial cell structure and function, eventually resulting in lower ventricular pumping function and heart failure. The incidence and mortality of heart failure is very high worldwide, being one of the most severe lethal diseases. In the United States, 30%-40% of the congestive heart failure (CHF) lead to hospitalization annually. Mortality 5 years after establishment of the diagnosis of CHF is 60% (male) and 45% (female). Mean survival time is 3.2 years (male) and 5.4 years (female), while the survival rate of patients with final stage CHF is only about 20%.
Neuregulin-1 (NRG-1), also named as Neu Differentiation Factor(NDF) or Glial Growth Factor (GGF), is a ligand of ErbB3 and ErbB4. The study in neuregulin gene defective mouse fetus demonstrates that neuregulin is essential for the development of heart and nervous system. However, the data are limited about the way neuregulin controls cell differentiation and downstream signal transduction. At early stage of heart development, neuregulin and ErbB receptor are expressed in the lining of endocardium and cardiac myocytes respectively. As these 2 layers are separated widely, neuregulin has to pass through the space between these 2 layers before it can activate ErbB receptor. The activation of ErbB receptors in cardiocyte is helpful for cardiocyte and its migration into endocardium. WO 00/37095 shows that neuregulin can enhance the differentiation of cardiac myocytes, strengthen the combination of sarcomere and cytoskeleton, as well as intercellular cohesion. WO 00/37095 also shows that neuregulin can be used to detect, diagnose and treat heart diseases. WO 00/37095 further shows that neuregulin and its analogues can promote cardiocyte differentiation in vitro, induce reconstruction of sarcomere and cytoskeleton in cardiocyte and intercellular cohesion, identify the polypeptide or compound that can inhibit neuregulin. The identified polypeptide or compound can be used to treat heart diseases and heart failure.
There exists a need in the art for more efficient and/or cost effective neuregulin related treatments for viral myocarditis, dilated cardiomyopathy, the cardiac toxicity of a prophylactic or therapeutic agent, e.g., ADM, without affecting its efficacy and myocardial infarction. The present invention addresses these and other related needs in the art.